Peter Attia MD"Anti-Aging" Drugs — NAD, metformin, & rapamycin | The Peter Attia Drive Podcast (Ep 207, AMA 35)
CHAPTERS
- 0:02 – 3:49
Why a Three-Person AMA on NAD, Rapamycin, and Metformin
The host Nick explains that this AMA bundles subscriber questions about three geroprotective molecules (NAD, rapamycin, metformin) and adds Matt Kaeberlein as a guest. Peter Attia had wanted to cover only NAD, while Matt argues for comparing all three.
- •Format is a three-person AMA, a first for the show
- •Questions compiled on NAD, rapamycin and metformin from past episodes
- •Peter initially preferred to focus only on NAD and its precursors
- •Matt wants a compare-and-contrast of the state of evidence for each class
- •Challenges of moving from lab to clinic are a theme
- 3:49 – 4:17
Are There Good Biomarkers of Aging?
Peter contrasts aging with lipidology, where ApoB is a clear biomarker, and says he doubts good aging biomarkers exist. Matt says what we want is something predictive of future outcomes, and that we are closer than 15–20 years ago but still a ways off.
- •ApoB is a clean causal biomarker in lipidology; aging lacks an equivalent
- •A biomarker should predict mortality, function and disease risk
- •Humans can eyeball relative health, implying underlying molecular signatures
- •Commercial aging clocks are now being sold to the public
- •The field has searched for molecular markers since the 1980s
- 4:17 – 12:51
Short-Term Readouts, Rate of Aging, and Functional Markers
Peter wishes for blood biomarkers that would show a response to a short intervention such as calorie restriction. Matt notes that markers of biological age may differ from markers of rate of aging, and favors functional biomarkers; Peter describes using functional and phenotypic measures in his practice.
- •Biomarkers of biological age may differ from biomarkers of rate of aging
- •Some interventions may reverse molecular and functional changes, not just slow aging
- •Matt favors functional measures of organ and tissue function
- •Improvement across multiple organs suggests modulating underlying aging biology
- •Peter tracks VO2 max, strength, muscle mass, glucose disposal, ApoB and inflammatory markers rather than epigenetic clocks
- 12:51 – 15:36
What Epigenetic Clocks Are and the Case for Them
Matt explains that epigenetic clocks use chemical modifications such as methylation to predict chronological age within about five years. Deviation from the best-fit line is taken as biologically older or younger, and longitudinal human studies link it to later disease and death risk.
- •Epigenetic marks are chemical changes to DNA or histones that control gene expression
- •Tens of thousands of marks change predictably with age
- •Algorithms predict chronological age within about plus or minus five years
- •People off the best-fit line may be biologically younger or older
- •Longitudinal studies show links to future disease and mortality
- 15:36 – 18:45
Limitations and the Missing Mouse Lifespan Experiment
Matt lists his concerns: about two dozen clocks, an environment that has changed over three decades, and no definitive experiment predicting outcomes. He and Peter discuss why no one has run the straightforward mouse lifespan study and what that experiment would look like.
- •About two dozen clocks exist and it's unclear which are best
- •Environmental change may alter which epigenetic marks matter for health
- •Matt is bothered that the mouse experiment hasn't been done
- •Proposed design: measure blood epigenetic age at 20 months, intervene, remeasure, then track survival and pathology
- •Individual-level prediction is what makes a clock useful
- 18:45 – 22:22
Epigenetic Clocks vs. Broader Aging Clocks
Peter asks about the difference between pure methylation clocks and algorithms that blend methylation with traditional biomarkers. Matt thinks broader clocks are likelier to work since epigenetics is only one hallmark of aging, while Peter doubts any signature will beat tried-and-true phenotypic tests.
- •Some clocks measure only DNA methylation; others combine many biomarkers
- •Epigenetics is only one of nine hallmarks of aging
- •Matt is more optimistic about broad aging signatures than methylation alone
- •Peter doubts a signature will outdo VO2 max, grip strength and muscle mass
- •Open question whether proteome and metabolome data are needed
- 22:22 – 25:53
Commercialization of Aging Clocks and Moving Goalposts
Peter warns of redefining a condition to fit a diagnostic test, using early cancer screening pitches as an example, and sees a parallel in pairing age clocks with supplements. Matt calls selling precise biological age measurement dishonest and says products claiming to reverse biological age are snake oil.
- •Early cancer detection companies claimed zero false positives by redefining cancer
- •Peter likens tuning clocks to interventions to drawing the target after shooting the arrow
- •Matt calls selling biological age tests to the public dishonest
- •Some argue it encourages healthy lifestyle choices, but Matt isn't sure
- •Matt says the FDA should step in on claims of reversing biological age
- 25:53 – 29:39
Transition to Interpreting Geroprotector Studies and Sneak Peek Wrap-Up
Nick asks how these biomarker caveats should shape how people read studies of geroprotective molecules in mice, yeast and humans. The episode then ends with the sneak peek message about membership for the full AMA.
- •Question on how to interpret studies of geroprotectors given biomarker limits
- •Request for strengths and limitations of model organisms and human studies
- •Full AMA is available to members
